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Accelerating resistance, inadequate antibacterial drug pipelines and international responses

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Abstract

The pandemic of multidrug-resistant (MDR) pathogens and their continuing spread is beyond dispute. In contrast to the past, today's antibacterial research and development (R&D) pipelines are nearly dry, failing to provide the flow of novel antibiotics required to match the clinical challenges of the multidrug resistance (MDR) crisis. Concerned over the rapidly worsening potential global healthcare crisis caused by MDR bacteria and the lack of robust drug pipelines, several multinational campaigns have issued policy recommendations and have initiated broad discussion with a goal of stimulating the development of novel antibacterial drugs and technologies. These activities have resulted in intensified co-operation between the USA and the EU. The recently announced extensive ‘Action plan against the rising threats from antimicrobial resistance’ substantially ramps up action within the EU. In recognising the potential crisis caused by MDR and the limited treatment options, the European Commission decided on an unprecedented approach to drive the search for novel antibiotics by integrating the pharmaceutical industry, the research capacities of universities and small companies supported by public funding along with pricing/reimbursement and regulatory bodies. The European Commission has shown leadership and put action plans in place. Only the future will tell whether these initiatives will help curb the impact of the MDR pandemic.

Introduction

Scientists have recognised resistance throughout the antibiotic era. In the past, a steady supply of new antibiotics effective against continuously emerging resistant strains adequately addressed resistance concerns. Nowadays, the combination of enormous selection pressure favouring not only bacteria with single but with multiple resistance determinants along with increasing worldwide mobility of people creates a fecund breeding ground for the multidrug resistance (MDR) pandemic. In alarming contrast to the past, today's antibacterial research and development (R&D) pipelines are nearly dry. The crisis created by escalating resistance in conjunction with a paucity of antibacterial innovation has long been recognised by the scientific and medical communities [1], [2]. As the MDR pandemic rapidly spreads globally, extensive international initiatives will be necessary to curb its consequences for patients and society.

This paper begins with a brief overview of the scope of the resistance problem and a prediction of the most important near-term resistance trends. This outlook for the continued escalation of resistance contrasts with the foreseeable inadequacy of antibacterial clinical development pipelines over the next 5–7 years. This paper provides an overview of the most concerning resistant bacteria as well as a brief review of the current antibacterial R&D scenario. Yet even as the gap between growing medical need and lean development pipelines widens, there is a glimpse of hope on the horizon as an international high-level response to the crisis shows promising leadership and the political will to address the crisis.

The international initiatives include a variety of measures to contain the MDR pandemic, including intensified survey, infection control, rapid diagnostics and antibiotic stewardship.

This paper closes with a summary of several recently published initiatives aimed at facilitating antibacterial R&D.

Section snippets

Accelerating resistance: a matter of concern

Society suffers from the indisputable and spreading pandemic of multidrug-resistant (MDR) pathogens placing a considerable burden on healthcare systems. For some of these infections, no active antibiotic is available. In the USA, >15% of healthcare-associated infections are caused by MDR bacteria [3]. These infections result in significantly higher total hospital costs along with increased length of hospital stay [4]. Estimates indicate that in 2007, ca. 25 000 European patients died from an

Escalating future resistance challenges: no good news

Resistance will continue to challenge our healthcare systems, and surprising adaptations of micro-organisms should be expected [9]. Within this overall context, the following key trends, ranked in order of importance, will substantially impact future treatment options.

What to expect: antibacterial pipelines

In the 1990s, with the pharmaceutical industry's focus on blockbuster drugs, most large pharmaceutical companies abandoned antibacterial R&D in favour of the far more lucrative chronic disease and life-style condition markets [27]. Years of low investment in antimicrobial drug R&D have now resulted in merely trickling antibacterial pipelines at the same time that antibiotic resistance has become a significant public health concern [28], [29]. In addition to these business and public health

Action is needed: the international response

In the face of lean antibacterial pipelines, the resistance problem has become such a large and urgent worldwide healthcare threat that only farsighted governments with the political will to act on a global scale in concert with all stakeholders will be able to provide an effective and adequate response [34]. With increasing frequency and urgency, major national and international healthcare organisations have been convening meetings of stakeholders and issuing policy reports that recognise the

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